Inflammation is a series of biological defensive responses caused by extrinsic irritative stimulation due to invasion of foreign materials (or bodies) into the body. In the above-mentioned series of biological defensive responses, the major responses include the increase of vascular permeability and infiltration of inflammatory cells, mainly of leukocytes. Autoimmune responses accompanied by intrinsic stimulation also induce inflammatory responses in addition to extrinsic stimulation due to allergenic substances (antigen) and bacteria. These inflammations induced by immune responses have been reported to cause inflammatory diseases through complicated processes. For example, inflammatory diseases of respiratory organs such as asthma and bronchitis are said to occur through two stages (see Medical Immunology, 15, 61-71 (1988)). That is, the first stage is a release of chemical mediators such as histamine and TXA.sub.2 from activated mast cell by extrinsic stimulation to result in the constriction of bronchial muscle. This first stage generally occurs within 30 minutes after the inhalation of antigens (exogenous stimulation) and is called immediate type asthma. The second stage is an invasion of eosinophiles (one type of leukocytes) into the lesion of bronchus followed by swelling of bronchial mucosa in the lesion by active oxygen produced by the eosinophile and results in the inflammation. This second stage occurs 8-16 hours after inhalation of antigens and is called delayed type asthma. Such inflammatory responses occurring by leukocytes are considered to make asthma intractable.
Heretofore, various drugs having specific antagonistic activity to chemical mediators such as histamine or TXA.sub.2 released from mast cell in the above-mentioned first stage have practically been used. These drugs are to be effective to ameliorate the symptoms in the first stage but insufficiently active to suppress the inflammation of the second stage, because various chemical mediators interact in the first stage and mere suppression of one specific factor (chemical mediator) among various ones can not sufficiently inhibit the progress into the second stage. Furthermore, these drugs have insufficient inhibitory effect against inflammation mainly due to leukocytes in the second stage. Thus, drugs which are antagonistic to various chemical mediators not only in the first stage, but also effective for suppression of inflammatory responses caused by leukocytes in the second stage have been desired.
In the other inflammatory diseases, leukocytes activated by stimulus have been reported to be a major cause of inflammatory responses. In pulmonary diseases such as adult respiratory distress syndrome (ARDS), leukocytes (neutrophils) are activated by endotoxin secreted from bacteria and play major role in inflammatory responses. The activated neutrophils adhere to pulmonary capillary vessels, and neutrophils release active oxygen and protease, damage capillary vessels and result in inflammation (see. Journal of Clinical and Experimental Medicine (IGAKU NO AYUMI), Special issue, Pulmonary Diseases, p. 437 (1991) pub. by Ishiyaku Publishers, Inc., Tokyo, Japan). In addition, arachidonic acid metabolites, such as TXA.sub.2, and LTs, such leukotriene B.sub.4, PAF and so on accelerate the tissue damages of vascular cells by neutrophils and exacerbate the inflammatory response. Autoimmune diseases caused by immunological mechanism accompanied by intrinsic stimulus, for example nephritis, are mainly caused by activated leukocytes (neutrophils). It is said that tissue damages caused by mediators such as active oxygen and TXA.sub.2 which are released from activated neutrophils result in nephritis when the neutrophils attack immune complex composed of antigen (glomerular basement membrane) and autoantibody to this. Many patients are suffering from various inflammatory diseases caused by inflammatory responses due to leukocytes, thus novel compounds useful for the treatment of inflammatory diseases and suppressants containing said novel compounds active against inflammatory diseases have been desired. Particularly, drugs which exhibit excellent suppressive effect for inflammatory responses due to leukocytes and inhibit the adhesion of leukocytes to the cells in the lesion have been desired.
The inventors of the present invention have been investigating novel compounds effective for inflammatory diseases and accomplished the present invention. That is, the present inventors synthesized novel compounds of purine derivatives shown by the general formula [I] below, evaluated their biological activities and found them to be effective for the suppression of inflammatory diseases and accomplished the present invention.